Inhibitors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma

ABSTRACT

The use of inhibitors of GSK-3 useful for treating glaucoma is disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of patent application Ser. No.10/488,496, filed Mar. 2, 2004 (now allowed), which claims priority fromPCT/US02/30059, filed Sep. 23, 2002, which claims priority fromProvisional Application Ser. No. 60/325,390 filed Sep. 27, 2001.

The present invention is directed to inhibitors of glycogen synthasekinase-3 for lowering and controlling normal or elevated intraocularpressure (IOP) and treating glaucoma.

BACKGROUND OF THE INVENTION

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated, but no apparent loss of visual function has occurred; suchpatients are considered to be a high risk for the eventual developmentof the visual loss associated with glaucoma. Some patients withglaucomatous field loss have relatively low intraocular pressure. Theseso called normotension or low tension glaucoma patients can also benefitfrom agents that lower and control IOP. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

There are some individuals who do not respond well when treated withcertain existing glaucoma therapies. There is, therefore, a need forother topical therapeutic agents that control IOP.

SUMMARY OF THE INVENTION

The present invention is directed to inhibitors of GSK-3 which can beused to treat glaucomatous optic neuropathy and/or lower and control IOPassociated with normal-tension glaucoma, ocular hypertension, and/orglaucoma in warm blooded animals, is including man. The compounds areformulated in pharmaceutical compositions suitable for topical deliveryto the eye.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Elevated intraocular pressure (IOP) is often an indicator of glaucoma.Left unchecked, continual and long term elevated IOP can contribute tothe progressive deterioration of the retina and the loss of visualfunction. Therefore, lowering IOP is often an objective in the treatmentof glaucoma patients in order to decrease the potential for or severityof glaucomatous retinopathy. It has been shown that even those glaucomapatients who do not exhibit elevated levels of IOP benefit from agentsthat lower and control IOP. Unfortunately, some individuals do notrespond well when treated with certain existing glaucoma therapies.

Wnt proteins comprise a large family of structurally related ligandsthat activate the Wnt signaling pathway. The frizzle family of proteinsare key components in this pathway serving as membrane bound receptorsfor Wnt. The frizzle proteins are a family of seven transmembraneproteins that have an N-terminal extracelluar cysteine rich domain and acytoplasmic carboxylate tail. Binding of Wnt to frizzle initiates acascade of events one of which results in the inhibition of (GSK-3)preventing the phosphorylation of β-catenin. Phosphorylation ofβ-catenin leads to its degradation. Activation of the Wnt pathwayincreases the intracellular concentration of uncomplexed β-catenin whichcan activate β-catenin-T cell factor/Lymphoid enhancer factor (TCF/Lef)dependent gene transcription.

Frizzle Related Proteins (FRP) are a family of secreted proteins withcysteine rich regions that are homologous to those of the frizzle familyof proteins but lack the membrane-spanning segments of the frizzleproteins. The secreted FRP acts to antagonize the Wnt signaling pathwayby binding extracelluar Wnt and preventing it from interacting withfrizzle proteins or by forming a nonfunctional complexes with thefrizzled receptor. Bafico et al. (1999).

Recently it has been discovered that frizzled related protein (FRP) isdifferentially expressed in a number of glaucomatous trabecular meshworkcell lines. Perfusion of FRP-1 through perfused human ocular anteriorsegments maintained in culture resulted in a decrease in flowrate and acorresponding decrease in β-catenin protein levels in the ciliary bodyand the trabecular meshwork (TM). The decreased flow rate in thecultured anterior segments models an increase in resistance to outflow(increase in intraocular pressure) in intact eye. These results showthat there is an active Wnt signaling pathway in the TM and ciliary bodyand suggest that this pathway is responsible at least in part formaintaining outflow through the TM and thereby controlling IOP.

Since the intracellular level of β-catenin is at least partiallyregulated by its phosphorylation by GSK-3, inhibition of GSK-3 resultsin the increase in uncomplexed soluble β-catenin irrespective of thelevels of FRP. GSK-3 inhibitors circumvent the FRP mediated antagonismof the Wnt signaling pathway caused by the elevated levels of FRP andcounteract the increase in outflow resistance that results from theincrease in production of FRP in individuals with glaucoma.

Increased expression of FRP was also detected in the retinas from humandonors having retinitis pigmentosa (RP). RP is a family of degenerativediseases that effect the photoreceptors and causes blindness. Since FRPstimulates apoptosis in neurons in vitro the presence of elevated FRPsuggests that FRP mediated disruption of Wnt signaling may be involvedin retinal degeneration. Although glaucoma is the selective loss ofretinal ganglion cells and not photoreceptor cells toxicity mediated byincreased expression of FRP or by other mechanism governed by a GSK-3mediated pathway may contribute to the loss of retinal ganglion cells inglaucoma. Therefore GSK-3 inhibitors would treat the loss of retinalganglion and also reduce intraocular pressure by increasing aqueoushumor outflow.

While not being bound by theory the inventors believe that inhibition ofGSK-3 will lower and control normal or elevated intraocular pressure(IOP) and treat is glaucomatous optic neuropathy. Compounds that act asGSK-3 inhibitors are well known and have shown a variety of utilities,primarily for disorders or conditions associated with diabetes,dementias such as Alzheimer's disease and manic depression. U.S. Pat.No. 6,057,117 discloses the use of selective inhibitors of GSK-3 for thetreatment of diseases that are mediated by GSK-3 activity includingdiabetes mellitus. WO 00/38675 discloses a method of treatment ofconditions associated with a need for the inhibition of GSK-3, such asdiabetes, conditions associated with diabetes, chronic neurodegenerativeconditions including dementias such as Alzheimer's disease, manicdepression, mood disorders such as schizophrenia, neurotraumaticdisorders such as acute stroke, hair loss and cancer. WO 00/21927discloses certain pyrrole-2,5-dione derivatives that are GSK-3inhibitors for the treatment of diabetes, dementias such as Alzheimer'sdisease and manic depression. WO 01/56567 describes 2,4-dimainothiazolederivatives and their use as GSK-3 inhibitors, WO 01/49709 describespeptide inhibitors of GSK-3, WO 01/47533 discloses the development ofmodulatory strategies for the treatment of various diseases. WO 01/41768discloses the use of hymenialdisine or derivatives for inhibiting cyclindependent kinases, GSK-3 beta and casein kinase 1 for treatingneurodegenerative disorders such as Alzheimer's disease, diabetes,inflammatory pathologies and cancers. WO 01/37819 discloses the use ofindirubine derivatives for making medicines inhibiting GSK-3 beta.

Certain paullones analogs have been reported (Leost et al. 2000) to beGSK-3 inhibitors. These compounds were proposed to be useful in thestudy and possible treatment of neurodegenerative and proliferativedisorders.

3-Anilino-4-arylmaleimides have been reported to be potent and selectiveinhibitors of GSK-3 (Smith et al. 2001).

Hymenialdisine is an inhibitor of GSK-3. It was suggested to havepotential in treating neurodegenerative disorders (Thunnissen et al.2000).

The protein kinase C inhibitors GF1092 and Ro 31-8220 have been reportedto be inhibitors of GSK-3 (Tavare et al. 1999).

Indirubines inhibit GSK-3 (Garnier et al. 2001). A potential applicationfor the use of the indirubines as a treatment of neurodegenerativedisorders was disclosed.

GSK-3 inhibitors SB-415286 and SB216763 protected both central andperipheral neurons grown in culture from death induced by reducedphosphatidyl inositol pathway activity (Cross et al. 2000).

The use of these compounds to lowering and controlling normal orelevated intraocular pressure (IOP) and to treat glaucoma has not beendisclosed.

This invention is directed at the treatment of glaucoma by theinhibition of GSK-3. It is contemplated that any GSK-3 inhibitingcompound will be useful in the methods of the present invention. Theinventors contemplate that any of the compounds disclosed in WO00/38675; WO 00/21927; Coglan et al. 2000; Leost et al. 2001; Smith etal. 2001; Garnier et al. 2001; Cross et al. 2001; Thunnissen et al.2000; Tavare et al. 1999 (as discussed above, all herein incorporated byreference) will be particularly useful.

In one preferred embodiment, the compound for use in the methods of theinvention will be selected from compounds defined in WO 00/21927, EP470490, WO 93/18766, WO 93/18765, EP 397060, WO 98/11103, WO 98/11102,WO 98/04552, WO 98/04551, DE 4243321, DE 4005970, DE 3914764, WO96/04906, WO 95/07910, DE 4217964, U.S. Pat. Nos. 5,856,517, 5,891,901,WO 99/42100, EP 328026, EP 384349, EP 540956, DE 4005969, or EP 508792.

Preferred compounds include compounds of the formula:

wherein R¹ and R² independently=

R³═H, C₁₋₆alkyl, (un)substituted phenyl, C₁₋₆alkyl-NR⁶R⁷,C₁₋₇cycloalkyl, C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷;

R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substituted phenyl,—OR⁶, —SR⁶, halogen, (un)substituted phenoxy, —CN, —NO₂,C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷, C₁₋₇cycloalkyl, (un)substituted heterocyclyl,—C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵, C₁₋₆alkylC(O)NR⁶R⁷; and

R⁵, R⁶, R⁷═H, C₁₋₆alkyl, (un)substituted phenyl.

Preferably,

R¹=A, B; R²=B, C;

R³═H, C₁₋₆alkyl, C₁₋₆alkyl-NR⁶R⁷, C₁₋₆alkyl-OR⁶, C₁₋₆alkylC(O)₂R⁵,C₁₋₆alkylC(O)NR⁶R⁷;R⁴═H, or one or more substituents C₁₋₆alkyl, (un)substituted phenyl,—OR⁶, halogen, (un)substituted phenoxy, —NO₂, C₁₋₆alkyl-NR⁶R⁷, —NR⁶R⁷,(un)substituted heterocyclyl, —C(O)₂R⁵, C₁₋₆alkylC(O)₂R⁵,C₁₋₆alkylC(O)NR⁶R⁷; and R⁵, R⁶, R⁷═H, C₁₋₃alkyl.

The most preferred compounds for use in the methods of the inventioninclude:

-   3-(1-[3-aminopropyl]-3-indoyl)-4-(2-chlorophenyl)pyrrole-2,5-dione    and-   3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.

In other embodiments, compounds useful in the methods of the inventionwill be selected from the indirubine analogs defined in WO 01/37819.Generally preferred compounds include indirubine,5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide) indirubine,indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and5-(dimethyl)sulfonamide indirubine.

Additional embodiments of the invention include the use of compoundsselected from the 2,4-diaminothiazole analog defined in WO 01/37819.Preferred compounds include:

-   (4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,-   (4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,-   (4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,-   1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one-   (4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,-   (4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,-   (4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,-   4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,-   [4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,-   (4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,-   (4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,-   (4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,-   (4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,-   (4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,-   (4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,-   1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,-   [4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,-   [4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,-   [4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,-   3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid    ethyl ester-   [4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,-   [4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,    and-   (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.

In still another embodiment, compounds selected from the1,2,4-triazole-carboxylic acid derivative or analog defined in WO01/09106 will be useful in the methods of the invention. Preferred1,2,4-triazole-carboxylic acid derivatives include:

-   3-amino-5-anilino-2-benzoyl-1,2,4-triazole,-   3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,-   3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,-   3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,-   3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,-   3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,-   3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,-   3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,-   3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,-   3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,-   3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,-   3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid    (4-phenoxyphenyl)amide,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid    (4-bromo-2-methylphenyl)amide,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid    (1-naphthyl)amide,-   3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid    (3-methoxyphenyl)amide,-   3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid    (4-chlorophenyl)amide, and-   3,5-diamino2-benzoyl-1,2,4-triazole.

Hymenialdisine or derivative or analog defined in WO 01/41768 may alsobe useful in certain embodiments of the invention. Preferred suchcompounds include:

-   Hymenialdisine    (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),-   4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,    and-   (4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.

Other embodiments of the invention include the use of paullone analogs,including 9-nitropaullone, 9-bromopaullone, 9-chloropaullone, and9-bromo-12-methoxycarbonylmethypaullone in the methods of the invention.

The Compounds of this invention, can be incorporated into various typesof ophthalmic formulations for delivery to the eye (e.g., topically,intracamerally, or via an implant). The Compounds are preferablyincorporated into topical ophthalmic formulations for delivery to theeye. The Compounds may be combined with ophthalmologically acceptablepreservatives, surfactants, viscosity enhancers, penetration enhancers,buffers, sodium chloride, and water to form an aqueous, sterileophthalmic suspension or solution. Ophthalmic solution formulations maybe prepared by dissolving a Compound in a physiologically acceptableisotonic aqueous buffer. Further, the ophthalmic solution may include anophthalmologically acceptable surfactant to assist in dissolving theCompound. Furthermore, the ophthalmic solution may contain an agent toincrease viscosity, such as, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose,polyvinylpyrrolidone, or the like, to improve the retention of theformulation in the conjunctival sac. Gelling agents can also be used,including, but not limited to, gellan and xanthan gum. In order toprepare sterile ophthalmic ointment formulations, the active ingredientis combined with a preservative in an appropriate vehicle, such as,mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gelformulations may be prepared by suspending the Compound in a hydrophilicbase prepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The Compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 4 to 8. The establishmentof a specific dosage regimen for each individual is left to thediscretion of the clinicians. The Compounds will normally be containedin these formulations in an amount 0.01% to 5% by weight, but preferablyin an amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0%by weight. The dosage form may be a solution, suspension microemulsion.Thus, for topical presentation 1 to 2 drops of these formulations wouldbe delivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

The Compounds can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers,prostaglandins, carbonic anhydrase inhibitors, α₂ agonists, miotics, andneuroprotectants.

The following examples are representative of the techniques employed bythe inventors in carrying out aspects of the present invention. Itshould be appreciated that while these techniques are exemplary ofpreferred embodiments for the practice of the invention, those of skillin the art, in light of the present disclosure, will recognize thatnumerous modifications can be made without departing from the spirit andintended scope of the invention.

EXAMPLE 1 GSK-3 Inhibition

Inhibition of GSK-3 can be assayed by the methods described in WO00/38675. Compounds are evaluated for their ability to inhibit thephosphorylation of a biotinylated peptide derived from the peptidesequence for the phosphorylation site of glycogen synthase.Biot-KYRRAAVPPSPSLSRHSSPHQ(SP)EDEEE is used as the substrate peptidewhere (SP) is a prephosphorylated serine and S are the three consensusphosphorylation sites for GSK-3 specific phosphorylation. GSK-3 kinase(10 nM final concentration) in a pH 7.0 MOPS buffer containing Tween-200.01%, glycerol 5%, 2-mercaptoethanol 7.5 mM, magnesium acetate 10 mM,substrate peptide 8 μM, [γ-³³P]-ATP 10 μM and inhibitor are incubated atroom temperature for 1 hour. The reaction is stopped by the addition ofan aqueous mM EDTA solution containing Strepavidin coated SPA beads.Following centrifugation radioactivity is counted using a betascintillation counter.

EXAMPLE 2 Inhibition of the FRP Induced Reduction in Outflow Rate andβ-catenin Levels in Perfused Anterior Segments

Human ocular anterior segments are perfused with Dulbecco's modifiedEagle's medium (DMEM) at a constant pressure of 11 mm Hg. The outflowrate of each eye is measured by weighing its reservoir at specifiedperiods. After a stabilization period, the eyes are perfused with eithervehicle or FRP-1 (10 μg/ml) and their outflow rates monitored for 2-5days. The perfusion of FRP-1 caused a decrease in aqueous humor outflow.Inhibitor is added and the anterior segment is perfused for anadditional 2-4 days. Outflow rate is measured by weighing its reservoirat specific periods.

EXAMPLE 3

Ingredients Amount (wt %) Compound of Example 1 0.01-2% ** Hydroxypropylmethylcellulose 0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodiumchloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 800.05% Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

EXAMPLE 4

Ingredients Amount (wt %) Compound of Example 1 0.01-2% Methyl cellulose4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5%Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkoniumchloride 0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to7.3-7.4 Purified water q.s. to 100%

EXAMPLE 5

Ingredients Amount (wt %) Compound of Example 1  0.01-2% Guar gum0.4-6.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5%Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkoniumchloride 0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to7.3-7.4 Purified water q.s. to 100%

EXAMPLE 6

Ingredients Amount (wt %) Compound of Example 1 0.01-2% White petrolatumand mineral oil and lanolin Ointment consistency Dibasic sodiumphosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetatedisodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically and structurallyrelated may be substituted for the agents described herein to achievesimilar results. Such substitutions and modifications apparent to thoseskilled in the art are deemed to be within the spirit, scope and conceptof the invention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

Patents

DE 3914764

DE 4005969

DE 4005970

DE 4217964

DE 4243321

EP 328026

EP 384349

EP 397060

EP 470490

EP 508792

EP 540956

U.S. Pat. No. 5,856,517

U.S. Pat. No. 5,891,901

U.S. Pat. No. 6,057,117

WO 93/18765

WO 93/18766

WO 95/07910

WO 96/04906

WO 98/04551

WO 98/04552

WO 98/11102

WO 98/11103

WO 99/42100

WO 00/21927

WO 00/38675

WO 01/09106

WO 01/37819

WO 01/41768

WO 01/47533

WO 01/49709

WO 01/56567

OTHER REFERENCES

Bafico et al., J. BIOL. CHEM., 274(23):16180-16187 (1999)

Leost et al., EUR. J. BIOCHEM., 267:5983-5994 (2001)

Smith et al., BIOORGANIC & MED. CHEM. LETTERS, 11:635-639 (2001)

Thunnissen et al., CHEM. & BIO., 7:51-63 (2000)

Tavare et al., FEBS LETTERS, 460:433-436 (1999)

Cross et al., J. NEUROCHEM., 77:94-102 (2001)

Coglan et al., CHEM. & BIO., 7(10):793-803 (2000)

Garnier et al., J. BIOL. CHEM., 276(1):251-260 (2001)

1-4. (canceled)
 5. A method for treating glaucomatous optic neuropathycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition comprising at least one glycogensynthase kinase-3 (GSK-3) inhibitor in a pharmaceutically acceptablecarrier, wherein said GSK-3 inhibitor is a compound selected from thegroup consisting of indirubine analogs, 2,4-diaminothiazole analogs,1,2,4-triazole-carboxylic acid derivatives or analogs, hymenialdesine orderivatives or analogs thereof, and paullone analogs.
 6. The method ofclaim 5, wherein the GSK-3 inhibitor is an indirubine analog.
 7. Themethod of claim 6, wherein the indrubine analog is selected from thegroup consisting of indirubine, 5-iodo-indirubine-3′monoxime,5-(hydroxyethylsulfonamide) indirubine, indirubine-3′-monoxime,5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamideindirubine.
 8. The method of claim 5, wherein the GSK-3 inhibitor is a2,4-diaminothiazole analog.
 9. The method of claim 8, wherein the2,4-diaminothiazole analog is selected from the group consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 10. The method ofclaim 5, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylic acidderivative or analog.
 11. The method of claim 10, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(4-phenoxyphenyl)amide, 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid (4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole.
 12. Themethod of claim 5, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 13. The method of claim 12, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of: Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.14. The method of claim 5, wherein the GKS-3 inhibitor is a paulloneanalog.
 15. The method of claim 14, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 16. The method of claim 1, wherein saidadministering is topical application, intracamerally or via an implant.17. The method of claim 1, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 18. (canceled) 19.(canceled)
 20. (canceled)
 21. (canceled)
 22. A method for loweringintraocular pressure (IOP) in a patient in need thereof comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a composition comprising at least one glycogen synthasekinase-3 (GSK-3) inhibitor in a pharmaceutically acceptable carrier,wherein said GSK-3 inhibitor is a compound selected from the groupconsisting of indirubine analogs, 2,4-diaminothiazole analogs,1,2,4-triazole-carboxylic acid derivatives or analogs, hymenialdesine orderivatives or analogs thereof, and paullone analogs.
 23. The method ofclaim 22, wherein the GSK-3 inhibitor is an indirubine analog.
 24. Themethod of claim 23, wherein the indrubine analog is selected from thegroup consisting of indirubine, 5-iodo-indirubine-3′monoxime,5-(hydroxyethylsulfonamide) indirubine, indirubine-3′-monoxime,5-(methyl)sulfonamide indirubine, and 5-(dimethyl)sulfonamideindirubine.
 25. The method of claim 22, wherein the GSK-3 inhibitor is a2,4-diaminothiazole analog.
 26. The method of claim 25, wherein the2,4-diaminothiazole analog is selected from the group consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 27. The method ofclaim 22, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylicacid derivative or analog.
 28. The method of claim 27, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(4-phenoxyphenyl)amide, 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid (4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole.
 29. Themethod of claim 22, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 30. The method of claim 29, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of: Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.31. The method of claim 22, wherein the GKS-3 inhibitor is a paulloneanalog.
 32. The method of claim 31, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 33. The method of claim 18, wherein saidadministering is topical application, intracamerally or via an implant.34. The method of claim 18, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 35. The method ofclaim 18, wherein said patient suffers from glaucoma or ocularhypertension.
 36. The method of claim 35, wherein said glaucoma isnormal-tension glaucoma.
 37. (canceled)
 38. (canceled)
 39. (canceled)40. (canceled)
 41. A method for preventing or inhibiting glaucomatousoptic neuropathy and controlling IOP in a patient in need thereof, saidmethod comprising administering to a patient in need thereof atherapeutically effective amount of a composition comprising at leastone glycogen synthase kinase-3 (GSK-3) inhibitor in a pharmaceuticallyacceptable carrier, wherein said GSK-3 inhibitor is a compound selectedfrom the group consisting of indirubine analogs, 2,4-diaminothiazoleanalogs, 1,2,4-triazole-carboxylic acid derivatives or analogs,hymenialdesine or derivatives or analogs thereof, and paullone analogs.42. The method of claim 41, wherein the GSK-3 inhibitor is an indirubineanalog.
 43. The method of claim 42, wherein the indrubine analog isselected from the group consisting of indirubine,5-iodo-indirubine-3′monoxime, 5-(hydroxyethylsulfonamide) indirubine,indirubine-3′-monoxime, 5-(methyl)sulfonamide indirubine, and5-(dimethyl)sulfonamide indirubine.
 44. The method of claim 41, whereinthe GSK-3 inhibitor is a 2,4-diaminothiazole analog.
 45. The method ofclaim 44, wherein the 2,4-diaminothiazole analog is selected from thegroup consisting of:(4-amino-2-phenylaminothiazol-5-yl)cyclopropylmethanone,(4-amino-2-phenylaminothiaol-5-yl)-(4-fluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)phenylmethanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-3-ylmethanone,1-(4-amino-2-phenylaminothiazol-5-yl)prpan-1-one(4-amino-2-phenylaminothiazol-5-yl)-3,4-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-fluorophenyl)methanone,(4-amino-2-phenylaminothazol-5-yl)naphthalen-2-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)biphenyl-4-ylmethanone,4-amino-2-phenylaminothiazol-5-yl)-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-bromophenylamino)thiazol-5-yl]cyclopropylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-3,4-dichlorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-3-methylbenzo[b]thiophen-2-yl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(3-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-methoxyphenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(4-chloro-3-methylphenyl)methanone,(4-amino-2-propylaminothiazol-5-yl)pyridin-3-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)pyridin-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)-pyridinyl-4-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-2-yl-methanone,(4-amino-2-phenylaminothiazol-5-yl)thiophen-3-ylmethanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-difluorophenyl)methanone,(4-amino-2-phenylaminothiazol-5-yl)-(2,6-dichlorophenyl)methanone,1-(4-amino-2-phenylaminothiazol-5-yl)ethanone,[4-amino-2(pyridin-3-ylamino)thiazol-5-yl]methanone,[4-amino-2-(pyrdin-3-ylamino)thiazol-5-yl]phenylmethanone,[4-amino-2-(3-methoxypropypylamino)thiazol-5-yl]pyridin-3-ylmethanone,3-[4-amino-5(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid ethylester[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,[4-amino-2-(4-chlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)methanone,and (4-amino-2-ethylaminothiazol-5-yl)phenylmethanone.
 46. The method ofclaim 41, wherein the GSK-3 inhibitor is a 1,2,4-triazole-carboxylicacid derivative or analog.
 47. The method of claim 46, wherein the1,2,4-triazole-carboxylic acid derivative or analog is selected from thegroup consisting of: 3-amino-5-anilino-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(3,4-methylenedioxybenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1-(3-trans-(2-furylacryloyl)1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid phenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid cyclohexylamide,3-amino-5-anilino-1,2,4-triazole-1-carboxylic acid cyclohexylamide,3-amino-5-(5-chloro-2-methylanilino)-2-benzoyl-1,2,4-triazole,3-amino-5-anilino-2-(4-chlorobenzoyl)1,2,4-triazole,3-amino-5-anilino-2-(2-naphthoyl)1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-phenylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-trifluoromethylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-((3-benzoyl)benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-biphenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(2-theinylacetyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-phenylthioacetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(phenoxybenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-benzoyl)-1,2,4-triazole,3-amino-5-anilino-2-cyclohexylcarbonyl-1,2,4-triazole,3-amino-5-anilino-2-phenylacetyl-1,2,4-triazole,3-amino-5-anilino-2-(3-nicotinyl)-1,2,4-triazole,3-amino-5-anilino-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-acetylbenzoyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-indolylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(4-fluorophenylacetyl)-1,2,4-triazole,3-amino-5-anilino-2-(3-bromobenzoyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyroyl)-1,2,4-triazole,3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoyl)-1,2,4-triazole,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid 4-biphenylamide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(4-phenoxyphenyl)amide, 3-amino-5-anilino-1,2,4-triazole-2-carboxylicacid (4-bromo-2-methylphenyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid (1-naphthyl)amide,3-amino-5-anilino-1,2,4-triazole-2-carboxylic acid(3-methoxyphenyl)amide,3-amino-5-(4-methoxyanilino)-1,2,4-triazole-2-carboxylic acid(4-chlorophenyl)amide, and 3,5-diamino2-benzoyl-1,2,4-triazole.
 48. Themethod of claim 41, wherein the GSK-3 inhibitor is a hymenialdisinederivative or analog.
 49. The method of claim 48, wherein thehymenialdesine derivative or analog is selected from the groupconsisting of: Hymenialdisine(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one),4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one,and(4-(2-amino-4-oxo-2-imidazolin-5-ylidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-c)azepine-8-one.50. The method of claim 41, wherein the GKS-3 inhibitor is a paulloneanalog.
 51. The method of claim 50, wherein the paullone analog isselected from the group consisting of 9-nitropaullone, 9-bromopaullone,9-chloropaullone, and 9-bromo-12-methoxycarbonylmethypaullone in themethods of the invention.
 52. The method of claim 37, wherein saidadministering is topical application, intracamerally or via an implant.53. The method of claim 37, wherein the concentration of said GSK-3inhibitor in said composition is from 0.01% to 2%.
 54. The method ofclaim 37, wherein said patient suffers from glaucoma or ocularhypertension.
 55. The method of claim 54, wherein said glaucoma isnormal-tension glaucoma.